Use of sulfoalkyl ether cyclodextrin as a preservative

Abstract

A method of preserving formulations is provided. The method includes the step of including a derivatized cyclodextrin in a formulation capable of sustaining microbial growth. One embodiment of the formulation employs a sulfoalkyl ether cyclodextrin as a preservative and optionally as a solubilizing and complexing agent. A suitable cyclodextrin is the CAPTISOL” brand cyclodextrin (sulfobutyl ether R-cyclodextrin). Whether or not the formulation includes a conventional preservative, the formulation will remain preserved for at least a minimum predetermined period. Specific embodiments of the invention include a carrier, a derivatized cyclodextrin and optionally one or more active agents, one or more water activity-reducing agents, and/or one or more complexation-enhancing agents. The derivatized cyclodextrin reduces the water activity of the formulation. A liquid formulation can be lyophilized or otherwise dried to yield a solid formulation that is optionally reconstitutable.

1 . A method of preserving a liquid formulation, capable of sustaining microbial growth, against microbial proliferation comprising the step of: 
 including a sulfoalkyl ether cyclodextrin in the formulation in an amount sufficient to preserve the formulation by at least reducing the rate of increase of microbial bioburden that may be present in the formulation during storage for at least a predetermined period of time, wherein the formulation optionally comprise at least one active agent and wherein the formulation remains preserved in the absence of a conventional preservative.    
     
     
         2 . The method of  claim 1 , wherein the cyclodextrin is present in an amount of at least about 25% wt/vol based upon the total volume of the formulation.  
     
     
         3 . The method of  claim 2 , wherein the cyclodextrin provides growth retarding, biostatic and/or biocidal properties to the formulation.  
     
     
         4 . The method of  claim 3 , wherein tee cyclodextrin at least reduce the rate of bioburden increase in the formulation as compared to a control formulation excluding the cyclodextrin.  
     
     
         5 . The method of  claim 3 , wherein the cyclodextrin at least maintains a substantially constant bioburden in the formulation during storage of the formulation.  
     
     
         6 . The method of  claim 3 , wherein the cyclodextrin at least reduces the bioburden of the formulation during storage of the formulation.  
     
     
         7 . The method of  claim 1 , wherein the cyclodextrin is present in an amount of at least about 25% wt/vol of the formulation and possesses biocidal activity.  
     
     
         8 . The method of  claim 1 , wherein the cyclodextrin is present in an amount of at least about 4.8% wt/vol of the formulation and possesses biostatic activity.  
     
     
         9 . The method of  claim 1  further comprising the step of including one or more water activity-reducing agents in the formulation.  
     
     
         10 . The method of  claim 2 , wherein the active agent is present and the cyclodextrin is present in molar excess over the active agent.  
     
     
         11 . The method of  claim 10 , wherein a mayor portion of the active agent is not complexed with the cyclodextrin.  
     
     
         12 . The method of  claim 10 , wherein a major portion of the active agent is complexed with the cyclodextrin by formation of an inclusion complex therewith and/or formation of a salt therewith.  
     
     
         13 . The method of  claim 10 , wherein the cyclodextrin increases the concentration of dissolved active agent in the formulation.  
     
     
         14 . The method of  claim 1  further comprising the step of sterile filtering the formulation through a filtration medium having a pore size of 0.1 microns or larger.  
     
     
         15 . The method of  claim 1  further comprising the step of isolating a reconstitutable solid from the liquid formulation, wherein the solid comprises an active agent, cyclodextrin and optionally a pharmaceutically acceptable excipient.  
     
     
         16 . The method of  claim 1  further comprising the step of purging the formulation with an inert pharmaceutically acceptable gas such that at least a substantial portion of the oxygen dissolved in the formulation is removed.  
     
     
         17 . The method of  claim 1 , wherein the formulation has a water activity of less than about 0.97±0.025.  
     
     
         18 . The method of  claim 1 , wherein the formulation has a water activity of less than about 0.95±0.025.  
     
     
         19 . The method of  claim 1 , wherein the formulation has a water activity of less than about 0.90±0.025.  
     
     
         20 . The method of  claim 1 , wherein the formulation has a water activity of less than about 0.85±0.025.  
     
     
         21 . The method of  claim 1 , wherein the formulation has a water activity of less than about 0.80±0.025.  
     
     
         22 . The method of  claim 1  further comprising the step of including a conventional preservative in the liquid formulation.  
     
     
         23 . The method of  claim 1  wherein the cyclodextrin is present in an amount of at least about 40%±2.5% wt/vol based upon the total volume of the formulation.  
     
     
         24 . The method of  claim 23 , wherein the cyclodextrin preserves the formulation at least against proliferation of one or more of  P. aeruginzosa, E. coli, S. aureus, C. albicans,  and  A. niger.    
     
     
         25 . The method of  claim 9 , wherein the one or more water activity-reducing agents is selected from the group consisting of poly(vinyl pyrrolidone) and poly(ethylene glycol).  
     
     
         26 . The method of claim  1 - 24  or  25  wherein the cyclodextrin is a compound of the Formula 1:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 4, 5 or 6;  
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each, independently, —O— a —O—(C 2 -C 6  alkylene)-SO 3   −  group, wherein at least one of R 1 —R 9  is independently a —O—(C 2 -C 6  alkylene)-SO 3   −  group, a —O—(CH 2 ) m SO 3   −  group wherein m is 2 to 6, —OCH 2 CH 2 CH 2 SO 3   − , or —OCH 2 CH 2 CH 2 CH 2 SO 3   − ); and  
 S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8  and S 9  are each, identify, a pharmaceutically acceptable cation.  
 
     
     
         27 . The method of  claim 26 , wherein the formulation further comprises at least one of antioxidant, buffing agent, acidifying agent, alkalizing agent, colorant, solubility-enhancing agent, complexation-enhancing agent, electrolyte, glucose, stabilizer, tonicity modifier, bulking agent, antifoaming agent, oil, emulsifying agent, cryoprotectant, plasticizer, flavor or sweetener.  
     
     
         28 . A method of unmasking a preservative property of an active agent not otherwise known to possess such property, the method comprising the step of exposing the active agent to sulfoalkyl ether cyclodextrin in an aqueous solution, optionally contaminate with a microbe, wherein the cyclodextrin is present in an amount sufficient to unmask a preservative property of the drug, and the drug is present in an amount sufficient to provide a preservative effect against a microbe in the solution.  
     
     
         29 . The method of  claim 28 , wherein the preservative property is selected from the group consisting of biocidal activity, growth retarding activity, biostatic activity, and a combination thereof.  
     
     
         30 . The method of  claim 29 , wherein the active agent is a phenol-based active agent.  
     
     
         31 . A method of preserving a liquid formulation comprising the step of: 
 including a sulfoalkyl ether cyclodextrin an optional active and a conventional preservative in the formulation wherein neither the cyclodextrin nor preservative is present in a soluble amount sufficient to preserve the formulation independently, but wherein the cyclodextrin and preservative cooperate to provide a preservative effect in the formulation.    
     
     
         32 . The method of  claim 31 , wherein the formulation is preserved by at least reducing the rate of increase of microbial bioburden that may be present in the formulation during storage for at least a predetermined period of time.  
     
     
         33 . The method of  claim 32 , wherein the cyclodextrin is present in an amount less than about 30% wt/vol based upon the final volume of the formulation.  
     
     
         34 . The method of  claim 32 , wherein the preservative and cyclodextrin together provide growth retarding, biostatic and/or biocidal properties to the formulation.  
     
     
         35 . The method of  claim 32 , wherein the preservative and cyclodextrin together at least reduce the rate of bioburden increase in the formulation as compared to a control formulation excluding the cyclodextrin and/or preservative.  
     
     
         36 . The method of  claim 32 , wherein the preservative and cyclodextrin together at least maintain a substantially constant bioburden in the formulation during storage of the formulation.  
     
     
         37 . The method of  claim 32 , wherein the preservative and cyclodextrin together at least reduce the bioburden of the formulation during storage of the formulation.  
     
     
         38 . The method of  claim 32 , wherein the active agent is present and the cyclodextrin is present in molar excess over the active agent.  
     
     
         39 . The method of  claim 38 , wherein a major portion of the active agent is not complexed with the cyclodextrin.  
     
     
         40 . The method of  claim 38 , wherein a major portion of the active agent is complexed with the cyclodextrin by formation of an inclusion complex therewith and/or formation of a salt therewith.  
     
     
         41 . The method of  claim 38 , wherein the cyclodextrin increases the concentration of dissolved active agent in the formulation.  
     
     
         42 . The method of  claim 32 , wherein the formulation has a water activity of less than about 0.97±0.025.  
     
     
         43 . The method of  claim 32 , wherein the formulation has a water activity of less than about 0.95±0.025.  
     
     
         44 . The method of  claim 32 , wherein the formulation has a water activity of less than about 0.90±0.025.  
     
     
         45 . The method of  claim 32 , wherein the formulation has a water activity of less than about 0.85±0.025.  
     
     
         46 . The method of  claim 32 , wherein the formulation has a Cater activity of less than about 0.80±0.025.  
     
     
         47 . The method of  claim 32 , wherein the preservative and cyclo dextrin together preserve the formulation at least against proliferation of one or more of  P. aeruginosa, E. coli, S. aureus, C. albicans, —and    A. niger.    
     
     
         48 . The method of  claim 32  wherein the formulation comprises one or more water activity reducing agents, and the one or more water activity-reducing agents is selected from the group consisting of poly(vinyl pyrrolidone) and poly(ethylene glycol).  
     
     
         49 . The method of claim  31 - 47  or  48 , wherein the cyclodextrin is a compound of the Formula 1:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 4, 5 or 6;  
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each, independently, —O— or a —O—(C 2 -C 6  alkylene)-SO 3   −  group, wherein at least one of R 1 —R 9  is independently a —O—(C 2 -C 6  alkylene)-SO 3   −  group, a —O—(CH 2 ) m SO 3   −  group wherein m is 2 to 6, —OCH 2 CH 2 CH 2 SO 3   − , or —OCH 2 CH 2 CH 2 CH 2 SO 3   − ); and  
 S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8  and S 9  are each, independently, a pharmaceutically acceptable cation.  
 
     
     
         50 . The method of  claim 49 , wherein the formulation further comprises at least one of antioxidant, buffing agent; acidifying agent, alkalizing agent, colorant, solubility-enhancing agent, complexation-enhancing agent, electrolyte, glucose, stabilizer, tonicity modifier, bulking agent, antifoaming agent, oil, emulsifying agent, cryoprotectant, plasticizer, flavor or sweetener.  
     
     
         51 . A method of preserving a liquid formulation comprising the step of: 
 including a cyclodextrin and/or cyclodextrin derivative, an optional active agent, and a water activity reducing agent in the formulation, wherein neither the cyclodextrin nor the water activity reducing agent is present in a soluble amount sufficient to preserve the formulation independently, but wherein the cyclodextrin and water activity reducing agent cooperate to provide a preservative effect in the formulation.    
     
     
         52 . The method of  claim 51 , wherein the cyclodextrin derivative is sulfoalkyl ether cyclodextrin.  
     
     
         53 . The method of  claim 51 , wherein the cyclodextrin is alpha, beta or gamma cyclodextrin.